{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T18:54:47Z","timestamp":1782586487043,"version":"3.54.5"},"reference-count":67,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T00:00:00Z","timestamp":1770249600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T00:00:00Z","timestamp":1770249600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100004473","name":"Sakarya University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004473","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Rheumatol Int"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The renin\u2013angiotensin system (RAS), traditionally regarded as a hormonal cascade regulating cardiovascular and renal homeostasis, is increasingly recognized as a locally active, tissue-specific network within joint structures. Accumulating evidence indicates that synovial tissue, synovial fluid, and articular cartilage harbor a functionally active joint-local renin-angiotensin system that operates partially autonomously from the systemic RAS circulation and is implicated in the pathogenesis of both arthritis (RA) and osteoarthritis (OA). This narrative review integrates human, animal, and in vitro evidence to examine the dual-axis organization of the joint RAS, comprising a pathogenic angiotensin-converting enzyme (ACE)\/Angiotensin II (Ang II)\/ Angiotensin II type 1 receptor (AT1R) axis and a counter-regulatory ACE2\/Angiotensin-(1\u20137) (Ang-(1\u20137))\/Mas receptor-Mas related G protein-coupled receptor D (Mas\u2013MrgD) axis, and to explore how imbalance between these pathways may differentially influence inflammatory and degenerative joint diseases. In RA, experimental and translational studies suggest that enhanced activity of the classical axis within synovial tissue is associated with synovial inflammation, fibroblast-like synoviocyte survival, angiogenesis, and bone erosion through pathways involving nuclear factor kappa B (NF-kB), mitogen-activated protein kinase (MAPK), and receptor activator of nuclear factor kB ligand (RANKL)\/Wingless-related integration site (Wnt) signaling pathway. In OA, available data indicate that chondrocyte expression of AT1R\/Angiotensin II type 2 receptor (AT2R), together with cytokine-induced receptor upregulation, may sensitize cartilage to Ang II-mediated effects, contributing to matrix metalloproteinase-13 (MMP-13)\u2013mediated matrix degradation and activation of interleukin-6 (IL-6)\/janus kinase 2 (JAK2)\/signal transducer and activator of transcription 3 (STAT3) signaling. Genetic studies support disease-specific patterns, with the ACE insertion\/deletion polymorphism showing a more consistent association with RA susceptibility than with knee OA, although findings vary across populations and do not consistently correlate with disease severity. From a therapeutic perspective, modulation of the joint-local RAS is currently supported mainly by preclinical evidence. Experimental models suggest that classical RAS inhibitors and emerging strategies targeting the protective axis\u2014such as putative ACE2 activators, AT2R agonists, and bone-targeted peptide delivery can influence inflammatory and structural pathways within the joint, while direct clinical evidence remains limited. Overall, current data support the biological relevance of a local joint RAS in arthritis pathophysiology and highlight key gaps between experimental findings and clinical translation.<\/jats:p>","DOI":"10.1007\/s00296-026-06073-9","type":"journal-article","created":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T04:19:43Z","timestamp":1770265183000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The joint-local renin\u2013angiotensin system in rheumatoid arthritis and osteoarthritis: mechanistic evidence, disease-specific patterns, and translational perspectives"],"prefix":"10.1007","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2260-4660","authenticated-orcid":false,"given":"Emre","family":"Bilgin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8028-9462","authenticated-orcid":false,"given":"\u0130brahim C.","family":"Haznedaro\u011flu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,5]]},"reference":[{"key":"6073_CR1","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1007\/s00424-024-02908-1","volume":"476","author":"H Triebel","year":"2024","unstructured":"Triebel H, Castrop H (2024) The Renin angiotensin aldosterone system. Pflugers Arch 476:705\u2013713. https:\/\/doi.org\/10.1007\/s00424-024-02908-1","journal-title":"Pflugers Arch"},{"key":"6073_CR2","doi-asserted-by":"publisher","first-page":"747","DOI":"10.1152\/physrev.00036.2005","volume":"86","author":"M Paul","year":"2006","unstructured":"Paul M, Poyan Mehr A, Kreutz R (2006) Physiology of local renin-angiotensin systems. Physiol Rev 86:747\u2013803. https:\/\/doi.org\/10.1152\/physrev.00036.2005","journal-title":"Physiol Rev"},{"key":"6073_CR3","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1016\/j.intimp.2019.04.023","volume":"72","author":"J Zhao","year":"2019","unstructured":"Zhao J, Yang H, Chen B, Zhang R (2019) The skeletal renin-angiotensin system: A potential therapeutic target for the treatment of osteoarticular diseases. Int Immunopharmacol 72:258\u2013263. https:\/\/doi.org\/10.1016\/j.intimp.2019.04.023","journal-title":"Int Immunopharmacol"},{"key":"6073_CR4","doi-asserted-by":"publisher","first-page":"6619","DOI":"10.1007\/s11033-021-06672-8","volume":"48","author":"FR Chaves Moreira","year":"2021","unstructured":"Chaves Moreira FR, de Oliveira TA, Ramos NE, Duarte Abreu MA, Simoes E, Silva AC (2021) The role of Renin angiotensin system in the pathophysiology of rheumatoid arthritis. Mol Biol Rep 48:6619\u20136629. https:\/\/doi.org\/10.1007\/s11033-021-06672-8","journal-title":"Mol Biol Rep"},{"key":"6073_CR5","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1038\/s41569-019-0244-8","volume":"17","author":"M Paz Ocaranza","year":"2020","unstructured":"Paz Ocaranza M, Riquelme JA, Garc\u00eda L, Jalil JE, Chiong M et al (2020) Counter-regulatory renin-angiotensin system in cardiovascular disease. Nat Rev Cardiol 17:116\u2013129. https:\/\/doi.org\/10.1038\/s41569-019-0244-8","journal-title":"Nat Rev Cardiol"},{"key":"6073_CR6","doi-asserted-by":"publisher","first-page":"964","DOI":"10.1161\/HYPERTENSIONAHA.123.21364","volume":"81","author":"M Bader","year":"2024","unstructured":"Bader M, Steckelings UM, Alenina N, Santos RAS, Ferrario CM (2024) Alternative renin-angiotensin system. Hypertension 81:964\u2013976. https:\/\/doi.org\/10.1161\/HYPERTENSIONAHA.123.21364","journal-title":"Hypertension"},{"key":"6073_CR7","doi-asserted-by":"publisher","first-page":"5037","DOI":"10.1007\/s10787-025-01890-z","volume":"33","author":"YH Habib","year":"2025","unstructured":"Habib YH, Khattab M, Gowayed MA (2025) The renin\u2013angiotensin system (RAS) and arthritic diseases: therapeutic potential for RAS inhibitors. Inflammopharmacology 33:5037\u20135047. https:\/\/doi.org\/10.1007\/s10787-025-01890-z","journal-title":"Inflammopharmacology"},{"key":"6073_CR8","doi-asserted-by":"publisher","first-page":"135","DOI":"10.55563\/clinexprheumatol\/kmmkj7","volume":"43","author":"Y Qian","year":"2025","unstructured":"Qian Y, Zhang B, Nian F (2025) The association between rheumatoid arthritis and left ventricular diastolic dysfunction: pathogenesis, predictors and managements. Clin Exp Rheumatol 43:135\u2013144. https:\/\/doi.org\/10.55563\/clinexprheumatol\/kmmkj7","journal-title":"Clin Exp Rheumatol"},{"key":"6073_CR9","doi-asserted-by":"publisher","first-page":"1409","DOI":"10.1007\/s00296-011-1999-3","volume":"31","author":"AY Gasparyan","year":"2011","unstructured":"Gasparyan AY, Ayvazyan L, Blackmore H, Kitas GD (2011) Writing a narrative biomedical review: considerations for authors, peer reviewers, and editors. Rheumatol Int 31:1409\u20131417. https:\/\/doi.org\/10.1007\/s00296-011-1999-3","journal-title":"Rheumatol Int"},{"key":"6073_CR10","doi-asserted-by":"publisher","first-page":"1060","DOI":"10.1016\/j.cjco.2021.04.004","volume":"3","author":"M Almutlaq","year":"2021","unstructured":"Almutlaq M, Alamro AA, Alroqi F, Barhoumi T (2021) Classical and counter-regulatory renin\u2013angiotensin system: potential key roles in COVID-19 pathophysiology. CJC Open 3:1060\u20131074. https:\/\/doi.org\/10.1016\/j.cjco.2021.04.004","journal-title":"CJC Open"},{"key":"6073_CR11","doi-asserted-by":"publisher","first-page":"e40725","DOI":"10.7759\/cureus.40725","volume":"15","author":"AK Kanugula","year":"2023","unstructured":"Kanugula AK, Kaur J, Batra J, Ankireddypalli AR, Velagapudi R (2023) Renin-angiotensin system: updated Understanding and role in physiological and pathophysiological States. Cureus 15:e40725. https:\/\/doi.org\/10.7759\/cureus.40725","journal-title":"Cureus"},{"key":"6073_CR12","doi-asserted-by":"publisher","first-page":"4981","DOI":"10.1182\/blood-2010-01-257287","volume":"115","author":"G Pejler","year":"2010","unstructured":"Pejler G, R\u00f6nnberg E, Waern I, Wernersson S (2010) Mast cell proteases: multifaceted regulators of inflammatory disease. Blood 115:4981\u20134990. https:\/\/doi.org\/10.1182\/blood-2010-01-257287","journal-title":"Blood"},{"key":"6073_CR13","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/ar1446","volume":"7","author":"PA Nigrovic","year":"2005","unstructured":"Nigrovic PA, Lee DM (2005) Mast cells in inflammatory arthritis. Arthritis Res Ther 7:1\u201311. https:\/\/doi.org\/10.1186\/ar1446","journal-title":"Arthritis Res Ther"},{"key":"6073_CR14","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1016\/j.joca.2023.01.005","volume":"31","author":"A Loucks","year":"2023","unstructured":"Loucks A, Maerz T, Hankenson K, Moeser A, Colbath A (2023) The multifaceted role of mast cells in joint inflammation and arthritis. Osteoarthritis Cartilage 31:567\u2013575. https:\/\/doi.org\/10.1016\/j.joca.2023.01.005","journal-title":"Osteoarthritis Cartilage"},{"key":"6073_CR15","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1111\/cei.12467","volume":"179","author":"Y Chang","year":"2015","unstructured":"Chang Y, Wei W (2015) Angiotensin II in inflammation, immunity and rheumatoid arthritis. Clin Exp Immunol 179:137\u2013145. https:\/\/doi.org\/10.1111\/cei.12467","journal-title":"Clin Exp Immunol"},{"key":"6073_CR16","doi-asserted-by":"publisher","first-page":"1417","DOI":"10.1172\/jci14276","volume":"109","author":"G Nguyen","year":"2002","unstructured":"Nguyen G, Delarue F, Burckl\u00e9 C, Bouzhir L, Giller T et al (2002) Pivotal role of the Renin\/prorenin receptor in angiotensin II production and cellular responses to Renin. J Clin Invest 109:1417\u20131427. https:\/\/doi.org\/10.1172\/jci14276","journal-title":"J Clin Invest"},{"key":"6073_CR17","doi-asserted-by":"publisher","first-page":"1086603","DOI":"10.3389\/fcvm.2023.1086603","volume":"10","author":"B Wang","year":"2023","unstructured":"Wang B, Jie H, Wang S, Dong B, Zou Y (2023) The role of (pro)renin receptor and its soluble form in cardiovascular diseases. Front Cardiovasc Med 10:1086603. https:\/\/doi.org\/10.3389\/fcvm.2023.1086603","journal-title":"Front Cardiovasc Med"},{"key":"6073_CR18","first-page":"251","volume":"23","author":"R Haque","year":"2017","unstructured":"Haque R, Iuvone PM, He L, Choi KSC, Ngo A et al (2017) The MicroRNA-21 signaling pathway is involved in prorenin receptor (PRR)-induced VEGF expression in ARPE-19 cells under a hyperglycemic condition. Mol Vis 23:251\u2013262 PMID:28465657","journal-title":"Mol Vis"},{"key":"6073_CR19","doi-asserted-by":"publisher","first-page":"33678","DOI":"10.1038\/srep33678","volume":"6","author":"O Domenig","year":"2016","unstructured":"Domenig O, Manzel A, Grobe N, K\u00f6nigshausen E, Kaltenecker CC et al (2016) Neprilysin is a mediator of alternative renin-angiotensin-system activation in the murine and human kidney. Sci Rep 6:33678. https:\/\/doi.org\/10.1038\/srep33678","journal-title":"Sci Rep"},{"key":"6073_CR20","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/BF00290326","volume":"13","author":"M Matucci-Cerinic","year":"1993","unstructured":"Matucci-Cerinic M, Lombardi A, Leoncini G, Pignone A, Sacerdoti L et al (1993) Neutral endopeptidase (3.4.24.11) in plasma and synovial fluid of patients with rheumatoid arthritis. A marker of disease activity or a regulator of pain and inflammation? Rheumatol Int 13:1\u20134. https:\/\/doi.org\/10.1007\/BF00290326","journal-title":"Rheumatol Int"},{"key":"6073_CR21","doi-asserted-by":"publisher","first-page":"1104","DOI":"10.1161\/circresaha.113.301077","volume":"112","author":"RQ Lautner","year":"2013","unstructured":"Lautner RQ, Villela DC, Fraga-Silva RA, Silva N, Verano-Braga T et al (2013) Discovery and characterization of alamandine: a novel component of the renin-angiotensin system. Circ Res 112:1104\u20131111. https:\/\/doi.org\/10.1161\/circresaha.113.301077","journal-title":"Circ Res"},{"key":"6073_CR22","doi-asserted-by":"publisher","first-page":"116480","DOI":"10.1016\/j.bcp.2024.116480","volume":"229","author":"NL Rukavina Mikusic","year":"2024","unstructured":"Rukavina Mikusic NL, Silva MG, Erra D\u00edaz FA, Pineda AM, Ferragut F et al (2024) Alamandine, a protective component of the renin-angiotensin system, reduces cellular proliferation and interleukin-6 secretion in human macrophages through MasR\u2013MrgDR heteromerization. Biochem Pharmacol 229:116480. https:\/\/doi.org\/10.1016\/j.bcp.2024.116480","journal-title":"Biochem Pharmacol"},{"key":"6073_CR23","doi-asserted-by":"publisher","unstructured":"de Carvalho Santuchi M, Dutra MF, Vago JP, Lima KM, Galv\u00e3o I et al (2019) Angiotensin-(1\u20137) and alamandine promote anti-inflammatory response in macrophages in vitro and in vivo. Mediators Inflamm 2019:2401081. https:\/\/doi.org\/10.1155\/2019\/2401081","DOI":"10.1155\/2019\/2401081"},{"key":"6073_CR24","doi-asserted-by":"publisher","first-page":"564","DOI":"10.3389\/fphar.2017.00564","volume":"8","author":"Y Wang","year":"2017","unstructured":"Wang Y, Del Borgo M, Lee HW, Baraldi D, Hirmiz B et al (2017) Anti-fibrotic potential of AT(2) receptor agonists. Front Pharmacol 8:564. https:\/\/doi.org\/10.3389\/fphar.2017.00564","journal-title":"Front Pharmacol"},{"key":"6073_CR25","doi-asserted-by":"publisher","first-page":"14849","DOI":"10.1073\/pnas.1101507108","volume":"108","author":"PM Abadir","year":"2011","unstructured":"Abadir PM, Foster DB, Crow M, Cooke CA, Rucker JJ et al (2011) Identification and characterization of a functional mitochondrial angiotensin system. Proc Natl Acad Sci U S A 108:14849\u201314854. https:\/\/doi.org\/10.1073\/pnas.1101507108","journal-title":"Proc Natl Acad Sci U S A"},{"key":"6073_CR26","doi-asserted-by":"publisher","first-page":"H2337","DOI":"10.1152\/ajpheart.2001.281.6.H2337","volume":"281","author":"C Berry","year":"2001","unstructured":"Berry C, Touyz R, Dominiczak AF, Webb RC, Johns DG (2001) Angiotensin receptors: signaling, vascular pathophysiology, and interactions with ceramide. Am J Physiol Heart Circ Physiol 281:H2337\u2013H2365. https:\/\/doi.org\/10.1152\/ajpheart.2001.281.6.H2337","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"6073_CR27","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1007\/s00296-004-0564-8","volume":"25","author":"V \u00c7obankara","year":"2005","unstructured":"\u00c7obankara V, \u00d6zt\u00fcrk MA, Kiraz S, Ertenli I, Haznedaroglu I et al (2005) Renin and angiotensin-converting enzyme (ACE) as active components of the local synovial renin-angiotensin system in rheumatoid arthritis. Rheumatol Int 25:285\u2013291. https:\/\/doi.org\/10.1007\/s00296-004-0564-8","journal-title":"Rheumatol Int"},{"key":"6073_CR28","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.amjms.2019.10.014","volume":"359","author":"Y Wu","year":"2020","unstructured":"Wu Y, Li M, Zeng J, Feng Z, Yang J et al (2020) Differential expression of renin-angiotensin system-related components in patients with rheumatoid arthritis and osteoarthritis. Am J Med Sci 359:17\u201326. https:\/\/doi.org\/10.1016\/j.amjms.2019.10.014","journal-title":"Am J Med Sci"},{"key":"6073_CR29","first-page":"632","volume":"20","author":"A Guy","year":"2018","unstructured":"Guy A, Sharif K, Bragazzi NL, Krosser A, Gilburd B et al (2018) Low levels of Renin and high aldosterone-to-renin ratio among rheumatoid patients and ankylosing spondylitis patients: A prospective study. Isr Med Assoc J 20:632\u2013636 PMID:30324781","journal-title":"Isr Med Assoc J"},{"key":"6073_CR30","doi-asserted-by":"publisher","first-page":"1252","DOI":"10.1093\/rheumatology\/kem092","volume":"46","author":"L Pattacini","year":"2007","unstructured":"Pattacini L, Casali B, Boiardi L, Pipitone N, Albertazzi L et al (2007) Angiotensin II protects fibroblast-like synoviocytes from apoptosis via the AT1-NF-\u03baB pathway. Rheumatology (Oxford) 46:1252\u20131257. https:\/\/doi.org\/10.1093\/rheumatology\/kem092","journal-title":"Rheumatology (Oxford)"},{"key":"6073_CR31","doi-asserted-by":"publisher","first-page":"1101","DOI":"10.1016\/j.jsps.2020.07.011","volume":"28","author":"AA Azouz","year":"2020","unstructured":"Azouz AA, Saleh E, Abo-Saif AA (2020) Aliskiren, tadalafil, and cinnamaldehyde alleviate joint destruction biomarkers; MMP-3 and RANKL; in complete freund\u2019s adjuvant arthritis model: downregulation of IL-6\/JAK2\/STAT3 signaling pathway. Saudi Pharm J 28:1101\u20131111. https:\/\/doi.org\/10.1016\/j.jsps.2020.07.011","journal-title":"Saudi Pharm J"},{"key":"6073_CR32","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1080\/14397595.2020.1740418","volume":"31","author":"NF Tomaz Braz","year":"2021","unstructured":"Tomaz Braz NF, Pinto MRC, Marciano Vieira EL, Souza AJ, Teixeira AL et al (2021) Renin-angiotensin system molecules are associated with subclinical atherosclerosis and disease activity in rheumatoid arthritis. Mod Rheumatol 31:119\u2013126. https:\/\/doi.org\/10.1080\/14397595.2020.1740418","journal-title":"Mod Rheumatol"},{"key":"6073_CR33","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1016\/j.intimp.2018.11.001","volume":"65","author":"Y Wang","year":"2018","unstructured":"Wang Y, Kou J, Zhang H, Wang C, Li H et al (2018) The renin-angiotensin system in the synovium promotes periarticular osteopenia in a rat model of collagen-induced arthritis. Int Immunopharmacol 65:550\u2013558. https:\/\/doi.org\/10.1016\/j.intimp.2018.11.001","journal-title":"Int Immunopharmacol"},{"key":"6073_CR34","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1007\/s00011-017-1069-8","volume":"66","author":"Y Zhang","year":"2017","unstructured":"Zhang Y, Luo X, Zhou Y, Wu H, Chen J et al (2017) 2K1C-activated angiotensin II (Ang II) exacerbates vascular damage in a rat model of arthritis through the ATR\/ERK1\/2 signaling pathway. Inflamm Res 66:881\u2013890. https:\/\/doi.org\/10.1007\/s00011-017-1069-8","journal-title":"Inflamm Res"},{"key":"6073_CR35","doi-asserted-by":"publisher","first-page":"648537","DOI":"10.1155\/2012\/648537","volume":"2012","author":"Y Kawakami","year":"2012","unstructured":"Kawakami Y, Matsuo K, Murata M, Yudoh K, Nakamura H et al (2012) Expression of angiotensin II receptor-1 in human articular chondrocytes. Arthritis 2012:648537. https:\/\/doi.org\/10.1155\/2012\/648537","journal-title":"Arthritis"},{"key":"6073_CR36","doi-asserted-by":"publisher","first-page":"105796","DOI":"10.1016\/j.intimp.2019.105796","volume":"75","author":"Y Wu","year":"2019","unstructured":"Wu Y, Lu X, Li M, Zeng J, Zeng J et al (2019) Renin-angiotensin system in osteoarthritis: A new potential therapy. Int Immunopharmacol 75:105796. https:\/\/doi.org\/10.1016\/j.intimp.2019.105796","journal-title":"Int Immunopharmacol"},{"key":"6073_CR37","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1177\/1076029616639704","volume":"22","author":"K Alexander","year":"2016","unstructured":"Alexander K, Banos A, Abro S, Hoppensteadt D, Fareed J et al (2016) Levels of matrix metalloproteinases in arthroplasty patients and their correlation with inflammatory and thrombotic activation processes. Clin Appl Thromb Hemost 22:441\u2013446. https:\/\/doi.org\/10.1177\/1076029616639704","journal-title":"Clin Appl Thromb Hemost"},{"key":"6073_CR38","first-page":"1088","volume":"38","author":"W Wang","year":"2020","unstructured":"Wang W, Han X, Zhao T, Zhang X, Qu P et al (2020) AGT, targeted by miR-149-5p, promotes IL-6-induced inflammatory responses of chondrocytes in osteoarthritis via activating the JAK2\/STAT3 pathway. Clin Exp Rheumatol 38:1088\u20131095 PMID:32141427","journal-title":"Clin Exp Rheumatol"},{"key":"6073_CR39","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1054\/mehy.1998.0830","volume":"54","author":"IC Haznedaroglu","year":"2000","unstructured":"Haznedaroglu IC, Arici M, B\u00fcy\u00fcka\u015fik Y (2000) A unifying hypothesis for the renin-angiotensin system and hematopoiesis: sticking the pieces together with the JAK-STAT pathway. Med Hypotheses 54:80\u201383. https:\/\/doi.org\/10.1054\/mehy.1998.0830","journal-title":"Med Hypotheses"},{"key":"6073_CR40","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1038\/s41584-021-00650-x","volume":"17","author":"K Ching","year":"2021","unstructured":"Ching K, Houard X, Berenbaum F, Wen C (2021) Hypertension Meets osteoarthritis - revisiting the vascular aetiology hypothesis. Nat Rev Rheumatol 17:533\u2013549. https:\/\/doi.org\/10.1038\/s41584-021-00650-x","journal-title":"Nat Rev Rheumatol"},{"key":"6073_CR41","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1007\/s00296-025-05891-7","volume":"45","author":"S Pimenta","year":"2025","unstructured":"Pimenta S, Gon\u00e7alves H, Pimenta M, Martins A, Costa L et al (2025) Central obesity and radiographic severity are associated with symptomatic hand osteoarthritis: a population-based cross-sectional study. Rheumatol Int 45:143\u2013155. https:\/\/doi.org\/10.1007\/s00296-025-05891-7","journal-title":"Rheumatol Int"},{"key":"6073_CR42","doi-asserted-by":"publisher","first-page":"2103","DOI":"10.2174\/138945011798829393","volume":"12","author":"M Luisa Bonet","year":"2011","unstructured":"Luisa Bonet M, Granados N, Palou A (2011) Molecular players at the intersection of obesity and osteoarthritis. Curr Drug Targets 12:2103\u20132128. https:\/\/doi.org\/10.2174\/138945011798829393","journal-title":"Curr Drug Targets"},{"key":"6073_CR43","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1111\/j.1756-185X.2012.01820.x","volume":"16","author":"AZ Ahmed","year":"2013","unstructured":"Ahmed AZ, El-Shahaly HA, Omar AS, Ghattas MH (2013) Patterns of angiotensin converting enzyme insertion\/deletion gene polymorphism among an Egyptian cohort of patients with rheumatoid arthritis. Int J Rheum Dis 16:284\u2013290. https:\/\/doi.org\/10.1111\/j.1756-185X.2012.01820.x","journal-title":"Int J Rheum Dis"},{"key":"6073_CR44","first-page":"2395","volume":"34","author":"SS Uppal","year":"2007","unstructured":"Uppal SS, Haider MZ, Hayat SJ, Abraham M, Sukumaran J et al (2007) Significant association of insertion\/deletion polymorphism of the angiotensin-converting enzyme gene with rheumatoid arthritis. J Rheumatol 34:2395\u20132399 PMID:17985406","journal-title":"J Rheumatol"},{"key":"6073_CR45","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1177\/1470320313478285","volume":"16","author":"GG Song","year":"2015","unstructured":"Song GG, Bae S-C, Kim J-H, Lee YH (2015) The angiotensin-converting enzyme insertion\/deletion polymorphism and susceptibility to rheumatoid arthritis, vitiligo and psoriasis: A meta-analysis. J Renin Angiotensin Aldosterone Syst 16:195\u2013202. https:\/\/doi.org\/10.1177\/1470320313478285","journal-title":"J Renin Angiotensin Aldosterone Syst"},{"key":"6073_CR46","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1615\/critrevimmunol.v28.i2.30","volume":"28","author":"Q Xiong","year":"2008","unstructured":"Xiong Q, Zhu J, Hasty KA, Canale ST, Stuart J et al (2008) The complexity in hunting for candidate genes within QTL that determine susceptibility to arthritis in rats. Crit Rev Immunol 28:127\u2013157. https:\/\/doi.org\/10.1615\/critrevimmunol.v28.i2.30","journal-title":"Crit Rev Immunol"},{"key":"6073_CR47","doi-asserted-by":"publisher","unstructured":"Ghelani AM, Samanta A, Jones AC, Mastana SS (2011) Association analysis of TNFR2, VDR, A2M, GSTT1, GSTM1, and ACE genes with rheumatoid arthritis in South Asians and Caucasians of East Midlands in the United Kingdom. Rheumatol Int 31:1355\u20131361. https:\/\/doi.org\/10.1007\/s00296-010-1478-2","DOI":"10.1007\/s00296-010-1478-2"},{"key":"6073_CR48","doi-asserted-by":"publisher","first-page":"e0161754","DOI":"10.1371\/journal.pone.016175","volume":"11","author":"C Lin","year":"2016","unstructured":"Lin C, Chen H-C, Fang W-H, Wang C-C, Peng Y-J et al (2016) Angiotensin-converting enzyme insertion\/deletion polymorphism and susceptibility to osteoarthritis of the knee: A case-control study and meta-analysis. PLoS ONE 11:e0161754. https:\/\/doi.org\/10.1371\/journal.pone.016175","journal-title":"PLoS ONE"},{"key":"6073_CR49","doi-asserted-by":"publisher","first-page":"2277","DOI":"10.1002\/jcp.27205","volume":"234","author":"R Ranjbar","year":"2019","unstructured":"Ranjbar R, Shafiee M, Hesari A, Ferns GA, Ghasemi F et al (2019) The potential therapeutic use of renin-angiotensin system inhibitors in the treatment of inflammatory diseases. J Cell Physiol 234:2277\u20132295. https:\/\/doi.org\/10.1002\/jcp.27205","journal-title":"J Cell Physiol"},{"key":"6073_CR50","doi-asserted-by":"publisher","first-page":"8127","DOI":"10.1007\/s00018-021-03983-8","volume":"78","author":"Y Chen","year":"2021","unstructured":"Chen Y, Sun H, Yao X, Yu Y, Tian T et al (2021) Pharmaceutical therapeutics for articular regeneration and restoration: state-of-the-art technology for screening small molecular drugs. Cell Mol Life Sci 78:8127\u20138155. https:\/\/doi.org\/10.1007\/s00018-021-03983-8","journal-title":"Cell Mol Life Sci"},{"key":"6073_CR51","first-page":"12584","volume":"8","author":"Y Tang","year":"2015","unstructured":"Tang Y, Hu X, Lu X (2015) Captopril, an angiotensin-converting enzyme inhibitor, possesses chondroprotective efficacy in a rat model of osteoarthritis through suppression local renin-angiotensin system. Int J Clin Exp Med 8:12584\u201312592 PMID:26550169","journal-title":"Int J Clin Exp Med"},{"key":"6073_CR52","doi-asserted-by":"publisher","first-page":"3965","DOI":"10.3892\/mmr.2017.7110","volume":"16","author":"K Yan","year":"2017","unstructured":"Yan K, Shen Y (2017) Aliskiren has chondroprotective efficacy in a rat model of osteoarthritis through suppression of the local renin-angiotensin system. Mol Med Rep 16:3965\u20133973. https:\/\/doi.org\/10.3892\/mmr.2017.7110","journal-title":"Mol Med Rep"},{"key":"6073_CR53","doi-asserted-by":"publisher","first-page":"1577","DOI":"10.1111\/jcmm.12128","volume":"17","author":"D Wang","year":"2013","unstructured":"Wang D, Hu S, Zhu J, Yuan J, Wu J et al (2013) Angiotensin II type 2 receptor correlates with therapeutic effects of Losartan in rats with adjuvant-induced arthritis. J Cell Mol Med 17:1577\u20131587. https:\/\/doi.org\/10.1111\/jcmm.12128","journal-title":"J Cell Mol Med"},{"key":"6073_CR54","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1186\/s40634-023-00673-1","volume":"10","author":"YH Habib","year":"2023","unstructured":"Habib YH, Sheta E, Khattab M, Gowayed MA (2023) Diminazene aceturate or Losartan ameliorates the functional, radiological and histopathological alterations in knee osteoarthritis rodent model: repurposing of the ACE2\/Ang1-7\/MasR cascade. J Exp Orthop 10:107\u2013123. https:\/\/doi.org\/10.1186\/s40634-023-00673-1","journal-title":"J Exp Orthop"},{"key":"6073_CR55","doi-asserted-by":"publisher","first-page":"1681","DOI":"10.3390\/pharmaceutics14081681","volume":"14","author":"A Ranjit","year":"2022","unstructured":"Ranjit A, Khajeh Pour S, Aghazadeh-Habashi A (2022) Bone-targeted delivery of Novokinin as an alternativetreatment option for rheumatoid arthritis. Pharmaceutics 14:1681. https:\/\/doi.org\/10.3390\/pharmaceutics14081681","journal-title":"Pharmaceutics"},{"key":"6073_CR56","doi-asserted-by":"publisher","first-page":"1157","DOI":"10.3390\/ph15091157","volume":"15","author":"SK Pour","year":"2022","unstructured":"Pour SK, Ranjit A, Summerill EL, Aghazadeh-Habashi A (2022) Anti-inflammatory effects of Ang-(1\u20137) bone-targeting conjugate in an adjuvant-induced arthritisrat model. Pharmaceuticals (Basel) 15:1157. https:\/\/doi.org\/10.3390\/ph15091157","journal-title":"Pharmaceuticals (Basel)"},{"key":"6073_CR57","doi-asserted-by":"publisher","first-page":"785744","DOI":"10.3389\/fmed.2021.785744","volume":"8","author":"B Soos","year":"2022","unstructured":"Soos B, Fagyas M, Horvath A, Vegh E, Pusztai A et al (2022) Angiotensin converting enzyme activity in anti-TNF-treated rheumatoid arthritis and ankylosing spondylitis patients. Front Med (Lausanne) 8:785744. https:\/\/doi.org\/10.3389\/fmed.2021.785744","journal-title":"Front Med (Lausanne)"},{"key":"6073_CR58","doi-asserted-by":"publisher","first-page":"1226760","DOI":"10.3389\/fmed.2023.1226760","volume":"10","author":"D Kacsandi","year":"2023","unstructured":"Kacsandi D, Fagyas M, Horvath A, Vegh E, Pusztai A et al (2023) Effect of Tofacitinib therapy on angiotensin converting enzyme activity in rheumatoid arthritis. Front Med (Lausanne) 10:1226760. https:\/\/doi.org\/10.3389\/fmed.2023.1226760","journal-title":"Front Med (Lausanne)"},{"key":"6073_CR59","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1056\/NEJMoa2109927","volume":"386","author":"SR Ytterberg","year":"2022","unstructured":"Ytterberg SR, Bhatt DL, Mikuls TR, Koch GG, Fleischmann R et al (2022) Cardiovascular and cancer risk with Tofacitinib in rheumatoid arthritis. N Engl J Med 386:316\u2013326. https:\/\/doi.org\/10.1056\/NEJMoa2109927","journal-title":"N Engl J Med"},{"key":"6073_CR60","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1136\/ard-2022-222259","volume":"82","author":"C Charles-Schoeman","year":"2023","unstructured":"Charles-Schoeman C, Buch MH, Dougados M, Bhatt DL, Giles JT et al (2023) Risk of major adverse cardiovascular events with Tofacitinib versus tumour necrosis factor inhibitors in patients with rheumatoid arthritis with or without a history of atherosclerotic cardiovascular disease: a post hoc analysis from ORAL surveillance. Ann Rheum Dis 82:119\u2013129. https:\/\/doi.org\/10.1136\/ard-2022-222259","journal-title":"Ann Rheum Dis"},{"key":"6073_CR61","doi-asserted-by":"publisher","first-page":"1194","DOI":"10.1002\/art.43188","volume":"77","author":"R Aymon","year":"2025","unstructured":"Aymon R, Mongin D, Guemara R, Salis Z, Askling J et al (2025) Incidence of major adverse cardiovascular events in patients with rheumatoid arthritis treated with JAK inhibitors compared with biologic disease-modifying antirheumatic drugs: data from an international collaboration of registries. Arthritis Rheumatol 77:1194\u20131204. https:\/\/doi.org\/10.1002\/art.43188","journal-title":"Arthritis Rheumatol"},{"key":"6073_CR62","doi-asserted-by":"publisher","first-page":"2007","DOI":"10.1007\/s00296-024-05659-5","volume":"44","author":"HJ Hinkema","year":"2024","unstructured":"Hinkema HJ, Westra J, Arends S, Brouwer E, Mulder DJ (2024) Higher levels of markers for early atherosclerosis in anti-citrullinated protein antibodies positive individuals at risk for RA, a cross sectional study. Rheumatol Int 44:2007\u20132016. https:\/\/doi.org\/10.1007\/s00296-024-05659-5","journal-title":"Rheumatol Int"},{"key":"6073_CR63","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1007\/s00296-025-05916-1","volume":"45","author":"L Murphy","year":"2025","unstructured":"Murphy L, Murphy G, Cornally N, McHugh S, Saab MM et al (2025) Low adherence to cardiovascular risk assessment guidelines in patients with rheumatoid arthritis: a retrospective chart review of routine clinical practice. Rheumatol Int 45:158. https:\/\/doi.org\/10.1007\/s00296-025-05916-1","journal-title":"Rheumatol Int"},{"key":"6073_CR64","doi-asserted-by":"publisher","first-page":"113307","DOI":"10.1016\/j.isci.2025.113307","volume":"28","author":"SA Groten","year":"2025","unstructured":"Groten SA, Langerhorst P, Malamas G, Barraclough A, Hoogendijk AJ et al (2025) Targeting synergetic endothelial inflammation by inhibiting NFKB and JAK-STAT pathways. iScience 28:113307. https:\/\/doi.org\/10.1016\/j.isci.2025.113307","journal-title":"iScience"},{"key":"6073_CR65","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1007\/s00296-025-05862-y","volume":"45","author":"P Anyfanti","year":"2025","unstructured":"Anyfanti P, Angeloudi E, Pagkopoulou E, Boutel M, Moysidou G-S et al (2025) Effects of treatment with Janus kinase inhibitors on coronary microvascular perfusion in patients with rheumatoid arthritis: an observational prospective cohort study. Rheumatol Int 45:111\u2013117. https:\/\/doi.org\/10.1007\/s00296-025-05862-y","journal-title":"Rheumatol Int"},{"key":"6073_CR66","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1302\/2046-3758.911.Bjr-2020-0022.R2","volume":"9","author":"J Seco-Calvo","year":"2020","unstructured":"Seco-Calvo J, Sanchez-Herraez S, Casis L, Valdivia A, Perez-Urzelai I et al (2020) Synovial fluid peptidase activity as a biomarker for knee osteoarthritis clinical progression. Bone Joint Res 9:789\u2013797. https:\/\/doi.org\/10.1302\/2046-3758.911.Bjr-2020-0022.R2","journal-title":"Bone Joint Res"},{"key":"6073_CR67","doi-asserted-by":"publisher","first-page":"3793","DOI":"10.3233\/thc-240317","volume":"32","author":"O Ciloglu","year":"2024","unstructured":"Ciloglu O, Karaali E, Yilmaz A, Cetinkaya PD, Unlu N et al (2024) Examination of SARS-CoV-2 RNA in joint synovial fluid of patients with COVID-19 and acute knee arthritis. Technol Health Care 32:3793\u20133800. https:\/\/doi.org\/10.3233\/thc-240317","journal-title":"Technol Health Care"}],"container-title":["Rheumatology International"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00296-026-06073-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00296-026-06073-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00296-026-06073-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T03:58:10Z","timestamp":1771646290000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00296-026-06073-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,5]]},"references-count":67,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["6073"],"URL":"https:\/\/doi.org\/10.1007\/s00296-026-06073-9","relation":{},"ISSN":["1437-160X"],"issn-type":[{"value":"1437-160X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,5]]},"assertion":[{"value":"28 November 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 January 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 February 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"None declared.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"As this work is a narrative review that does notinvolve human participants or original patient data, ethical approval andinformed consent were not required.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}],"article-number":"43"}}